Hepatitis is a serious world-wide health problem. Approximately 200 million people are chronically infected with hepatitis B virus, and large numbers of deaths are attributed to fulminant hepatitis, cirrhosis, and hepatocellular carcinoma. Although an effective subunit vaccine has been produced, limitations in supply and expense have prevented its global use. As an alternative, we are trying to construct a live recombinant hepatitis B vaccine. The gene for hepatitis B virus surface antigen has bene engineered and inserted inot the genome of vaccinia virus. The recombinant vaccinia virus is stable and expresses the hepatitis virus protein. The latter is glycosylated, assembled into particles and transported through the plasma membrane of infected cells. Rabbits vaccinated with the recombinant virus produced a high and sustained specific antibody response. Vaccination of chimpanzees resulted in priming of the immune system and protection against clinical hepatitis upon subsequent challenge with hepatitis B virus. Recombinant vaccinia viruses that express pre-S as well as S antigens are being evaluated. Additional recombinant vaccinia viruses that express genes of hepatitis delta virus, a naturally occurring defective virus of man have also been made.